SUMMARY Scientific advances in HIV treatment have demonstrated that immediate access to combination antiretroviral therapy (ART) provides both individual and public health benefits. With sufficient uptake of ART, HIV-related morbidity, mortality and transmission can be drastically reduced at the population-level. As a result, the focus of global HIV control strategies have turned towards efforts to ?seek, test, treat and retain? people living with HIV (PLHIV) in ART. Emerging research on the cascade of HIV care, a simple metric tracking numbers of individuals infected, diagnosed, on ART and virally suppressed, has made clear that the control of the HIV epidemic hinges on the performance of health care systems in reaching and delivering care to PLHIV. Yet, as a surveillance tool, it provides an incomplete and possibly misleading basis for decisions on how to allocate funding. The US HIV epidemic is a diverse set of microepidemics, dispersed primarily across large urban centers with different underlying epidemiological and structural conditions. These disparate underlying conditions require localized strategies to optimize the HIV care cascade. Changes over time in these microepidemics, as well as in evidence on how to improve HIV testing and care, challenges our ability to make informed and timely decisions that result in the greatest health benefits for the resources invested in treating and preventing HIV. We propose a novel economic modeling framework to revolutionize HIV surveillance. This framework would ensure scarce resources are focused on interventions that can provide the greatest value for money in a given microepidemic. We will build upon a validated economic model to produce rapid, automated evidence synthesis, focusing on minimal data requirements to update the model, and integrate findings from emerging results of public health interventions into real-time disease surveillance systems. Experimental and observational studies of interventions to improve HIV testing and ART engagement have demonstrated their effectiveness in generalized and targeted populations, yet they are vastly underused in practice. Structural interventions for people who inject drugs (PWID), such as needle exchange and opioid agonist therapy (OAT), have proven incredibly valuable in jurisdictions with low barriers to these services, resulting in staggering declines in HIV incidence and disease burden. We hypothesize that a unique mix of these interventions will provide the best value for money in each microepidemic, and that the optimal combinations will change over time according to underlying epidemic trends and the state of scientific advancement in HIV intervention research. We will demonstrate our approach for six distinct urban settings in the US with disparate structural conditions, substance use patterns, and HIV epidemics. This project is an innovative translational research initiative that will enhance surveillance efforts and increase the impact of interventional research in HIV and substance use disorders.